Preparation Of Multifunctional Parthenolide Liposomes And Study On Their Synergetic Antitumor Effects

The high incidence and mortality of malignant tumors have seriously threatened human health.In order to overcome the obstacles of cancer treatment,nano drug delivery system(NDDS)combining nanotechnology and traditional chemotherapy drugs have attracted the attention worldwide.In this study,natural plant extract of parthenolide(PTL)was used as basic chemotherapeutic drug,and nanoliposomes were used as drug carriers.We had prepared PTL liposome drug delivery system with nano-gold sphere shell structure for dual response of p H and near-infrared light,nano magnetic targeting liposomes with dual encapsulated PTL and indocyanine green(ICG),magnetic particle-coated PTL/glucose oxidase(GOD)liposome drug delivery system based on tumor microenvironment.The respective antitumor mechanisms were also explored.The research contents are as follows:(1)PTL liposomes were synthesized by ethanol injection method,and combined with chitosan(CS)by positive and negative charges.Subsequently,PTL liposomes with nano-gold shell structure(PTL-Lips@CS@GNS)were successfully synthesized by seed growth method by combining CS with Au-NH₂.Under acidic conditions,CS could achieve amino protonation and achieve p H-responsive releasing.Photothermal conversion was performed under the irradiation of 808nm near-infrared light(NIR)by SPR,which could achieve photothermal therapy(PTT).The local high temperature changed the phase of the liposome phospholipid membrane,released the drug,and achieved the NIR responsive releasing.Under the conditions of p H 5.5 and laser irradiation,the drug release could reach more than80%.The results of experiments in vitro and in vivo indicated that the synergistic effect of PTL chemotherapy and PTT treatment could achieve outstanding tumor inhibition effect.(2)MNPs were prepared by co-precipitation method,then ICG-PTL-Lips was synthesized by ethanol injection method.MNPs were modified on the surface of ICG-PTL-Lips to prepare ICG and PTL dual loading and magnetic targeting liposome drug delivery system(ICG-PTL-Lips@MNPs).Under NIR irradiation,ICG not only achieved the therapeutic effect of PTT,but also achieved the effect of photodynamic therapy(PDT).The saturation magnetization of the magnetic liposomes was 25.9 emu/g,which met the conditions of superparamagnetism and had a magnetic targeting function.In the study of photothermal properties,ICG-PTL-Lips@MNPs nanoparticles were clearly aggregated in the region of the magnet,which improved the local photothermal conversion efficiency,and its cumulative drug release was as high as 93.30%.In in vitro,synergistic inhibition rate of ICG-PTL-Lips@MNPs under laser irradiation was 75.5%,and the inhibition rate of PTT plus PDT induced by NIR laser alone was 36.5%.In the cell uptake experiment,magnet plus laser irradiation improved the uptake efficiency.With the synergistic effects of chemotherapy,PTT,PDT and magnetic targeting,ICG-PTL-Lips@MNPs had also shown excellent tumor inhibition effect and good biological safety in vivo.(3)The microenvironment of tumor tissue exhibits hypoxia,low p H,and overexpression of H₂O₂,which provides conditions for Fe₃O₄magnetic nanoparticles to perform chemodynamic therapy(CDT)based on Fenton reaction.Thin film hydration method was used to prepare GOD-PTL-Lips@MNPs coated magnetic nanoparticles with biocatalytic function.Glucose oxidase(GOD)could catalyze glucose to producte more H₂O₂ and lower the p H,which could amplify CDT treatment.By cell experiments in vitro,ROS fluorescent probes confirmed that more·OH was produced,and the effect of CDT treatment was significantly increased.At the same time,when measuring intracellular GSH,PTL as a chemotherapeutic drug,could consume a large amount of GSH in the cells,reduce the antioxidant function of the cells,and improved the efficacy of CDT.By the antitumor experiment in vivo,GOD-PTL-Lips@MNPs could generate·OH in situ and achieve a triple-coordinated treatment of chemotherapy,CDT,and hunger treatment under the action of magnets.In MRI performance testing,T₂-weighted imaging of GOD-PTL-Lips@MNPs in vitro showed excellent effect,and also provided a good tracking effect in vivo.In summary,the three multifunctional nano drug delivery systems synthesized in this study not only improved the effective utilization of chemotherapeutic drugs,but also realized the synergistic effects of controlled release of drugs,PTT treatment,PDT treatment,CDT treatment,and magnetic targeting.The antitumor mechanisms were also studied,which laid the foundation for related research.